Managing Immune-Related Toxicities

San Francisco, CA—Many patients with advanced melanoma or advanced lung cancer have benefited from treatment with checkpoint inhibitors, which have helped extend survival to previously unthinkable lengths. Although the impression is that checkpoint inhibitors are free of adverse events, in reality, clinicians strive daily to balance the efficacy and toxicity of these treatments.

At the 2016 Palliative Care in Oncology Symposium, Lynn Schuchter, MD, Chief, Division of Hematology Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, described common toxicities of the 4 immune checkpoint inhibitors—ipilimumab, nivolumab, pembrolizumab, and atezolizumab—recently approved by the FDA, and her approach to managing these adverse events.

Nonspecific Toxicities

Before each dose of a checkpoint inhibitor, patients should be evaluated for toxicities, advised Dr Schuchter. Although immune-related adverse events are generally mild (ie, grade 1 or 2), with longer follow-up more uncommon toxicities can emerge, including epi­scleritis, uveitis, pancreatitis, nephritis, neuropathies, and cardiomyopathies.

“Essentially any organ can be affected by autoimmune complications. I have seen 2 patients have wonderful responses to treatment and then die from cardiomyopathy,” Dr Schuchter told attendees.

Initial management of toxicities usually starts with eliminating other noninflammatory causes and assessing severity. For mild and tolerable symptoms, treatment can typically be continued. With moderate reactions, Dr Schuchter will often hold or omit a dose and begin systemic corticosteroids (ie, 0.5-1.0 mg/kg daily of prednisone or an equivalent agent).

“With anti–PD-1/PD-L1 antibodies, doses are not reduced; rather, schedules are adjusted. When symptoms resolve or return to baseline, steroids can be slowly tapered and treatment can usually be resumed,” Dr Schuchter emphasized.

When symptoms are severe, therapy should be permanently discontinued and systemic corticosteroids, 1 to 2 mg/kg daily, should be initiated.

Specific Symptom Management

Rash and pruritus

Patients who experience pruritus will report itchy skin, but rash may not be obvious, said Dr Schuchter, who recommended supportive measures, such as antihistamines or topical steroids, and sun protection for mild pruritus.

For a confluent rash, the recommendation is to withhold treatment and consider oral steroids. If the rash is severe, treatment should be discontinued and steroids continued, often intravenously.

Diarrhea and colitis

Because of the risk for peritonitis, perforation, and life-threatening complications, diarrhea and especially colitis are the most concerning toxicities, and patients should immediately report changes in bowel movements, said Dr Schuchter.

Abdominal pain, mucus or blood in the stool, peritoneal signs, bowel perforations, and ileus are high-risk signs that require urgent care, and colitis may warrant hospitalization for intravenous fluids and steroids.

Dr Schuchter approaches patients with diarrhea by first ruling out Clostridium difficile. When drug-related colitis is diagnosed, therapy is individualized. Mild illness is treated with supportive care and increased monitoring. More serious illness is treated as follows:

Stools <4× baseline: loperamide, budesonide

Stools <7× baseline: 1 mg/kg prednisone

Stools >7× baseline or refractory to oral steroids, hospitalize for intravenous methylprednisolone sodium succinate (Solu-Medrol) 1 to 2 mg/kg; consider colonoscopy and computerized tomography scan for further evaluation; and consider the use of infliximab 5 mg/kg.

Endocrinopathy and hypophysitis

Patients should have a chemistry panel, including thyroid-stimulating hormone, at baseline and with each treatment, but a pituitary gland panel is not necessary unless hypophysitis is suspected based on magnetic resonance imaging, said Dr Schuchter.

Headache related to these conditions can be treated with high-dose steroids. When the thyroid or pituitary gland is affected, the change may be permanent, but early intervention with high-dose steroids during acute hypophysitis may preserve pituitary gland function.

Endocrinopathy management starts with replacing the missing hormones—levothyroxine for thyroid deficiencies, and low-dose hydrocortisone for pituitary gland dysfunction. Clinicians should be aware of the potential for adrenal crisis and advise patients to wear medical alert bracelets, Dr Schuchter noted.

Hepatotoxicity

Liver function should be evaluated before each dose. Mild enzyme elevations can be managed with frequent monitoring. Treatment should be held, and monitoring increased, when enzymes exceed 2.5 to 5.0 times the upper limit of normal (ULN), or when bilirubin is more than 1.5 to 3.0 times the ULN. When levels rise higher than this, however, the drug should be permanently discontinued and steroids should be initiated.

Pneumonitis

Pneumonitis, a potentially life-threatening event, is more common in patients who receive anti–PD-1 agents (eg, pembrolizumab or nivolumab) rather than cytotoxic T-lymphocyte antigen 4 inhibitors (eg, ipilimumab). Pneumonitis can present with cough or with shortness of breath, and can be confused with lung metastases.

If pneumonitis is isolated and patients are asymptomatic, treatment can be continued with close observation, said Dr Schuchter.

For symptomatic patients, treatment should be withheld and high-dose steroids should be started. Patients with severe symptoms or with hypoxia should be hospitalized, treated with steroids, and considered for bronchoscopy.

After severe pneumonitis, reinitiating treatment may not be possible.

“Prolonged use and slow taper of steroids can result in its own consequences, including risk of atypical infections, compression fractures, and other steroid-related side effects. Vigilance for these complications is also part of the long-term management of these patients,” Dr Schuchter pointed out.